The long term goals of this proposal are to elucidate the functions of the short chain and medium chain carnitine acyltransferases and acylcarnitines that occur in mammalian systems and to characterize the biochemical processes involved.
The specific aims are: 1) to characterize the purified soluble carnitine octanyltransferase and acetyltransferase mouse liver peroxisomes, 2) to determine the basis for the kinetic and functional differences of the two forms of carnitine palmityltransferase associated with the inner mitochondrial membrane using purified COT/CPT from beef heart mitochondria, 3) to continue characterizing the changes in short chain acylcarnitines which occur in biological tissues subjected to various physiological states, 4) to determine the effect of carnitine on specific aliphatic acylCoAs and the effect of carnitine on the CoASH/acylCoA ratio in the matrix of isolated mitochondria, and 5) to characterize the metabolic fate acetylcarnitine. These studies should provide a better understanding of the metabolic abnormalities which occur as a consequence of carnitine deficiency in humans. Since the major metabolic fuels (glucose, fatty acids, and some amino acids, i.e, branched chain ones and glutamate) all have terminal oxidation steps in the matrix of mitochondria which require CoASH and all have key enzymes effected or regulated by the CoASH/acylCoA ratio, low levels of carnitine should produce a diversity of metabolic profiles depending on the enzyme affected and fuel sources available. The investigations with beef heart COT/CPT should provide new information about the mechanism of the selection of acyl residues oxidized by mitochondria when mixtures of acylCoA derivatives are present. The studies with the purified peroxisomal carnitine acetyl transferase and carnitine octanyltransferase from mouse liver could provide insight into the function of these enzymes in vivo. The studies with radioactive acetylcarnitine in mice should provide direct evidence concerning the metabolic fate of the compound.
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